Synthetic oligonucleotides with immunostimulatory sequences (ISS) containing unmethylated CpG dinucleotides mimic the innate recognition of microbial DNA and show great promise as adjuvants and immune modulators in a wide variety of therapeutic settings. In addition to their ability to activate multiple components of innate immunity, ISS have shown the ability to "prime" the innate immune system to give enhanced innate and subsequent adaptive responses to a number of bacterial and viral pathogens (3). This can lead to enhanced resistance to both lethal and sublethal challenges. A single administration of ISS in animal models can provide measurable protection for two to four weeks and increased resistance can be maintained with periodic administration of ISS. Prophylactic vaccination through the innate immune system has significant potential as a first-line defense for populations threatened with exposure to bioterrorism/biowarfare agents or exotic or emerging infectious diseases. This proposal is for the development of an inhaled form of ISS as a prophylaxis for airborne infectious agents. We currently are developing 1018 ISS for treatment of asthma and have completed preclinical development and Phase I safety studies in man. The current studies would provide a set of proof-of-principle studies for its use as an inhaled prophylactic and would generate a set of surrogate assays that would be essential for clinical development for this indication.